Targeting Cancer miRNAs by Adoptive Transfer of Programmed B Lymphocytes

通过程序化 B 淋巴细胞的过继转移靶向癌症 miRNA

基本信息

批准号：
8893915
负责人：
MAURIZIO ZANETTI
金额：
$ 16.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893915
关键词：
Adoptive Transfer B-Cell Lymphomas B-Lymphocytes Biological Models Breast Cancer Cell Breast cancer metastasis CMV promoter Cancer Cell Growth Cells Development Down-Regulation Engineering Future Gene Targeting Genomics Goals Growth Health Hematologic Neoplasms Hybrids In Vitro Injection of therapeutic agent Laboratories Laboratory Finding Leukemic Cell Link Lung Lymphocyte Malignant Neoplasms Manuscripts Measurement Metastatic breast cancer Methods MicroRNAs Modality Mus NOD/SCID mouse Nature Neoplasm Metastasis Normal Cell Oncogenes Oncogenic Pilot Projects Plasmid Cloning Vector Plasmids Regulation Replacement Therapy Solid Neoplasm Solutions Spleen Testing Therapeutic Transgenic Organisms Untranslated RNA Validation Vertebral column Work base cancer cell cancer therapy congenic design high risk in vivo innovation migration neoplastic cell novel strategies outcome forecast overexpression programs research study restoration success tumor tumor progression tumorigenic uptake

项目摘要

DESCRIPTION (provided by applicant): This laboratory recently discovered that primary B-lymphocytes can be programmed for the synthesis and delivery of short, non-coding RNAs in vitro and in vivo. In this revised R21 application we intend to rapidly adapt this new concept and test it in the context of tumor therapy to limit or control cancer cell growth and metastasis. miRNA "signatures" have been identified in both hematological malignancies and solid tumors, distinguishing tumor cells from normal cells. In some instances miRNAs are associated with the prognosis and the progression of cancer. This can happen because of one of two conditions: loss of suppressor miRNAs or overexpression of oncogenic miRNAs. miRNA-based therapy can then be geared at either restore the loss of a particular miRNA or suppress an oncogenic miRNA, respectively. The present proposal aims at gathering first line proof-of-concept that primary B lymphocytes synthesizing and secreting short, non-coding miRNAs can be used to treat cancer in vivo, a new form of therapy that we have termed immunogenomic therapy to typify its hybrid (genomic and immunological) nature. The following three Aims are proposed: (1) Engineer and characterize therapeutic plasmid vectors for miRNA replacement or inhibition; (2) miRNA inhibition: Targeting miR-155 in B leukemic cells; and (3) miRNA replacement: Restoring miR-335 in metastatic breast cancer cells. It is hoped that the work proposed in this high risk/high pay off revised proposal will provide us with the answers needed for a proof-of-principle validation of the new idea. We anticipate that success in obtaining proof-of-concept validation for immunogenomic therapy will open new horizons for the treatment of cancer and metastases.

描述（由申请人提供）：该实验室最近发现，可以在体外和体内对主要的B淋巴细胞进行编程以合成和递送简短的非编码RNA。在此修订后的R21应用中，我们打算快速适应这一新概念，并在肿瘤治疗的背景下对其进行测试，以限制或控制癌细胞的生长和转移。在血液恶性肿瘤和实体瘤中都已经鉴定出miRNA“特征”，从而将肿瘤细胞与正常细胞区分开。在某些情况下，miRNA与癌症的预后和进展有关。这可能是由于两个条件之一而发生的：抑制器miRNA的丧失或致癌miRNA的过表达。然后，基于miRNA的治疗可以分别恢复特定miRNA的损失或抑制致癌miRNA。本提案旨在收集一线概念概念，即原代B淋巴细胞合成和分泌短的，非编码的miRNA可用于在体内治疗癌症，这是一种新型的治疗形式，我们称为免疫基因组疗法，以典型地构成其混合（基因组和免疫学）性质。提出了以下三个目的：（1）工程师和表征miRNA替代或抑制作用的治疗质粒向量；（2）miRNA抑制作用：靶向miR-155在白血病细胞中；（3）miRNA替代：恢复转移性乳腺癌细胞中的miR-335。希望在这项高风险/高薪修订的提案中提出的工作将为我们提供对新想法的原理证明所需的答案。我们预计，在获得免疫基因组疗法的概念验证验证方面的成功将为治疗癌症和转移的治疗开辟新的视野。